Chronic kidney disease (CKD), also known as chronic renal disease (CRD) affects about 10% of the population in Europe and North America. CKD is characterized by a progressive loss in renal function over a period of months or years. The Kidney Disease Improving Global Outcomes (KDIGO) statement has defined CKD as either kidney damage or reduced glomerular filtration rate (GFR) to less than 60 mL/min/1.73 m2 sustained for more than 3 months (cf. KDIGO Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD, Kidney Int 76; Suppl. 113, 2009). There is no specific treatment unequivocally shown to slow the worsening of CDK except for cases where there is a specific underlying cause to CKD such as vasculitis. A permanent kidney failure then requires a renal replacement therapy which may be a form of dialysis or a kidney transplant. As CKD progresses and GFR declines, mineral metabolism disturbances increase and hyperphosphatemia occurs along with a reduction in renal 1a-hydroxylation of 25-hydroxyvitamin D and low circulating levels of calcitriol which in turn cause a decrease of intestinal calcium absorption. The disturbed calcium and phosphate homeostasis causes variable degrees of hypocalcemia and secondary hyperparathyroidism, with concomitant abnormalities in bone turnover and metabolic bone disease. The mineral and bone disorder (MBD) is a common manifestation of CKD. Other symptoms of CKD include increase blood pressure, iron deficiency anaemia, metabolic acidosis, azotemia and uraemia, an activation of the sympathetic tone, inflammation and oxidative stress. CDK goes therefore in line with high morbidity and mortality. CKD patients suffer in particular from accelerated atherosclerosis and tissue calcification. CKD patients on dialysis or with end stage renal disease (ESRD) are more likely to die from cardiovascular complications than from kidney failure (Kettler M et al, Nephrology 2009, 14: 389-394).
The progress of arterial and vascular calcification is linked to a dysregulated mineral metabolism and altered levels of serum calcium and calcium-phosphorus products. The elevated extracellular levels of these minerals further affect the survival and phenotype of vascular smooth muscle cells and myocardial cells. The calcification, mostly as calcium hydroxyl apatite deposits, may occur in blood vessels, the myocardium and cardiac valves. In the arterial vessel wall, calcification takes place in the intima or In the media. Medial calcification (also referred to as Monckeberg sclerosis) is the form classically associated with age, diabetes and CKD.
Conventional therapeutic approaches are usually directed to bringing the biochemical parameters to ranges associated with lower mortality. They comprise (a) a use of an adapted dialysate calcium concentration; (b) a use of phosphate-binding agents; (c) the administration of calcitriol or vitamin D analogues; (d) the use of calcimimetics; (d) diet recommendations (reducing dietary phosphate intake and administering phosphate binders and calcium supplements); and/or (e) the uptake of native vitamin D supplements. WO 2011/000086 A1 (University of Alberta) discloses an method and apparatus for reducing serum phosphate levels and calcium product in patients by hemodialysis since observational data suggest that higher doses of calcium-based phosphate binders may contribute to vascular calcification. There is generally a considerable interest in controlling serum phosphate while minimizing oral calcium load. On the other hand, most phosphate is intracellular and thus unavailable to hemodialysis. WO 2011/130528 A (Fresenius Medical Care Holdings Inc., US) discloses an extracorporeal blood treatment system including a calcium trap wherein an immobilized species is adapted to reduce the calcium concentration in the blood to a concentration that prevents blood clotting thereby producing calcium-depleted blood. However, there are no specific drugs or intervention methods available for interfering with the pathogenesis of vascular and tissue calcification. There is also a need for more drugs and intervention methods against the cardiovascular risks concomitant CKD, ESRD and renal replacement therapies. The prior art therefore represents a problem.